BACKGROUND: The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. However, the genetic predisposing factors to ESCC in this region have not been clearly defined. The P21(waf1/cip1) gene is involved in the arrest of cellular growth, as induced by the p53 tumor suppressor gene. Two polymorphisms of p21 gene in codon 31 (p21 C98A, dbSNP rs1801270) and the 3'UTR (p21 C70T, dbSNP rs1059234) may affect protein expression and play a role in cancer susceptibility. The present study aimed to investigate the association of p21 polymorphisms in codon 31 and the 3'UTR, and cigarette smoking on the risk of ESCC in northeastern Iran.METHODS: A case-control study was carried out to detect the p21 polymorphism in the 3'UTR and codon 31 of samples from 126 ESCC cases and 100 controls from 2006 to 2007. There were no significant differences of age and sex between cases and controls. Genotyping of p21 polymorphisms were determined with the PCR-RFLP method. Conditional logistic regression was used to adjust for potential confounders.RESULTS: None of the p21 genotypes were significantly associated with risk of ESCC, even after adjusting for age and gender (P=0.52, OR=1.24; 95%CI: 0.63-2.42). However, the presence of these polymorphisms in combination with cigarette smoking had a synergistic interaction in ESCC carcinogenesis in northeastern Iran (P=0.02, OR=8.38; 95%CI: 1.03-67.93).CONCLUSION: Our data suggests that these two p21 polymorphisms, both alone and in combination, are not genetic susceptibility biomarkers for ESCC. However, their interaction with cigarette smoking may influence the susceptibility to ESCC development in northeastern Iran.